AUTHOR=Aquino Nunez Wendy , Combs Benjamin , Gamblin T. Chris , Ackley Brian D. 

TITLE=Age-dependent accumulation of tau aggregation in Caenorhabditis elegans

JOURNAL=Frontiers in Aging

VOLUME=Volume 3 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/aging/articles/10.3389/fragi.2022.928574

DOI=10.3389/fragi.2022.928574

ISSN=2673-6217

ABSTRACT=Aging is the primary risk factor for Alzheimer's disease (AD) and related disorders (ADRDs). Tau aggregation is a hallmark of AD and other tauopathies. Even in normal aging, tau aggregation is found in brains, but in disease states, significantly more aggregated tau is present in brain regions demonstrating synaptic degeneration and neuronal loss. It is unclear how tau aggregation and aging interact to give rise to the phenotypes observed in disease states. Most AD/ADRD animal models have focused on late stages, after significant tau aggregation has occurred, but there are fewer where we can observe the early aggregation events and progression during aging. To address this gap, we created C. elegans models expressing a GFP-tagged version of the human tau protein. Here we examined in vivo aggregation of wild-type tau (hTau40), a disease-associated mutation (P301S), or an aggregation-prone variant (3PO) during aging. We measured age-dependent changes in GFP intensity and correlated those changes to normal aging in the nematode. We found differences in tau stability and accumulation depending on the tau variant expressed. hTau40GFP and P301SGFP were filamentous and localized to axons and cell bodies. The 3POGFP was more punctate in axons with extensive inclusions of GFP within cell bodies. Expression of 3POGFP resulted in decreased lifespan, consistent with a proteotoxic effect. Finally, we found that the human tau interacted genetically with the C. elegans ortholog of human tau, ptl-1. The loss of ptl-1 resulted in differences in tau accumulation, depending on the variant used, and it significantly accelerated the time to death in animals expressing 3PO.